UCS1025 derivatives

ABSTRACT

UCS 1025 derivatives having antitumor activity or antibacterial activity which are represented by formula (I): 
                 
 
wherein R 1  represents hydrogen, lower alkyl, etc.; R 2  represents hydrogen, or is combined with R 3  to represent a bond, etc., or is combined with R 4  to represent —O(C═O)—, etc.; R 3  represents hydrogen, etc., or is combined with R 2  to represent a bond, etc.; R 4  represents hydrogen, etc., or is combined with R 2  to represent —(C═O)O—, etc.; R 5  represents hydrogen or is combined with R 6  to represent a bond; R 6  represents hydrogen, etc., or is combined with R 5  to represent a bond; R 7  represents hydrogen or is combined with R 8  to represent ═O; R 8  represents hydroxy or is combined with R 7  to represent ═O;  ----  represents a single bond or a double bond, and a represents a single bond (two carbon atoms to which a is bound are combined to form a single bond) or an oxygen atom, or pharmaceutically acceptable salts thereof.

TECHNICAL FIELD

The present invention relates to UCS 1025 derivatives having antitumoractivity or antibacterial activity.

BACKGROUND ART

Examples of known compounds in which the 1-position of a decalin ringand the 3-position of 2-pyrrolidone are bound via carbonyl includeZG-1494α having a platelet-activating factor acetyltransferaseinhibitory activity which is represented by formula (II):

(J. Antibiotics, 49, 967-973 (1996)), oteromycin having an endothelinreceptor antagonistic activity which is represented by formula (III):

(J. Org. Chem., 60, 7040-7042 (1995)) and the like.

Examples of known compounds having a pyrrolizidinone skeleton includepyrrolam A represented by formula (IV):

(Liebig. Ann. Chem., 525-530 (1990)), compounds represented by formulae(V) to (VIII)

(Liebig. Ann. Chem., 381-385 (1988)) and the like, but antibacterial andantitumor activities are not known in each of the above-mentionedcompounds.

As a compound having antibacterial activity, F-12434 represented byformula (IX):

is known (Japanese Published Unexamined Patent Application No.227514/97), and, as compounds having antibacterial activity andantitumor activity, UCS 1025A represented by formula (X) wherein R ishydrogen and UCS 1025B represented by formula (X) wherein R is hydroxy:

are known (Japanese Published Unexamined Patent Application No.245385/98).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel UCS 1025derivatives having excellent antitumor activity or antibacterialactivity.

The present invention relates to UCS 1025 derivatives represented byformula (I):

-   -   wherein R¹ represents hydrogen, lower alkyl, NR⁹R¹⁰ (wherein R⁹        and R¹⁰ are the same or different and each represents hydrogen,        substituted or unsubstituted lower alkyl, substituted or        unsubstituted lower alkenyl, substituted or unsubstituted lower        alkynyl, substituted or unsubstituted aryl, substituted or        unsubstituted aralkyl or OR¹¹ (wherein R¹¹ represents hydrogen        or lower alkyl), or R⁹ and R¹⁰ are combined together with the        adjacent N to form a substituted or unsubstituted heterocyclic        ring), SR¹² (wherein R¹² represents hydrogen, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        alkenyl, substituted or unsubstituted lower alkynyl, substituted        or unsubstituted aryl, or substituted or unsubstituted aralkyl)        or OR¹³ (wherein R¹³ represents hydrogen, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        alkenyl, or substituted or unsubstituted lower alkynyl),    -   R² represents hydrogen, is combined with R³ to represent a bond,        —O— or —CH═N—NH— (R² binds at the CH side of —CH═N—NH— and R³        binds at the NH side of —CH═N—NH—, respectively), or is combined        with R⁴ to represent —O(C═O)—(R² binds at the O side of —O(C═O)—        and R⁴ binds at the (C═O) side of —O(C═O)—, respectively) or        —NR¹⁴(C═O)— (R² binds at the NR¹⁴ side of —NR¹⁴(C═O)— and R⁴        binds at the (C═O) side of —NR¹⁴(C═O)—, respectively; and R¹⁴        represents hydrogen, substituted or unsubstituted lower alkyl,        substituted or unsubstituted lower alkenyl, substituted or        unsubstituted lower alkynyl, substituted or unsubstituted aryl,        or substituted or unsubstituted aralkyl),    -   R³ represents hydrogen, OR¹⁵ (wherein R¹⁵ represents hydrogen,        substituted or unsubstituted lower alkyl, substituted or        unsubstituted lower alkenyl, substituted or unsubstituted lower        alkynyl, substituted or unsubstituted aralkyl, or substituted or        unsubstituted lower alkanoyl) or halogen, or is combined with R²        to represent a bond, —O— or —NH—N═CH— (R³ binds at the NH side        of —NH—N═CH— and R² binds at the CH side of —NH—N═CH—,        respectively),    -   R⁴ represents hydrogen, CO₂R¹⁶ (wherein R¹⁶ represents hydrogen,        substituted or unsubstituted lower alkyl, substituted or        unsubstituted lower alkenyl, substituted or unsubstituted lower        alkynyl, substituted or unsubstituted aryl, or substituted or        unsubstituted aralkyl) or CONR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ are the        same or different and each represents hydrogen, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        alkenyl, substituted or unsubstituted lower alkynyl, substituted        or unsubstituted aryl, or substituted or unsubstituted aralkyl,        or R¹⁷ and R¹⁸ are combined together with the adjacent N to form        a substituted or unsubstituted heterocyclic ring), or is        combined with R² to represent —(C═O)O— (R⁴ binds at the (C═O)        side of —(C═O)O— and R² binds at the O side of —(C═O)O—,        respectively) or —(C═O)NR¹⁴— (R⁴ binds at the (C═O) side of        —(C═O)NR¹⁴ and R² binds at the NR¹⁴ side of —(C═O)NR¹⁴—        respectively; and R¹⁴ has the same meaning as defined above),    -   R⁵ represents hydrogen or is combined with R⁶ to represent a        bond,    -   R⁶ represents hydrogen or OR¹⁹ (wherein R¹⁹ has the same meaning        as the above R¹⁵), or is combined with R⁵ to represent a bond,    -   R⁷ represents hydrogen or is combined with R⁸ to represent ═O,    -   R⁸ represents hydroxy or is combined with R⁷ to represent ═O,    -   ---- represents a single bond or a double bond, and    -   a represents a single bond (two carbon atoms to which a is bound        are combined to form a single bond to thereby form a double        bond) or an oxygen atom,    -   with the proviso that        1) a compound in which R² and R⁴ are combined to represent        —O(C═O)—, R¹ represents hydrogen, R³ represents hydrogen or        hydroxy, R¹ represents hydrogen, R⁶ represents hydroxy, R⁷ and        R⁸ are combined to represent ═O, and ---- and a represent a        single bond, and        2) a compound in which R¹ represents hydrogen, R² and R³ are        combined to represent a bond, R⁴ represents carboxy, R⁵        represents hydrogen, R⁶ represents hydroxy, R⁷ and R⁸ are        combined to represent ═O, and ---- and a represent a single bond        are excluded, or    -   pharmaceutically acceptable salts thereof.

The present invention relates to UCS 1025 derivatives, wherein, informula (I), R⁴ is hydrogen, CO₂R¹⁶ (wherein R¹⁶ has the same meaning asdefined above) or CONR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ have the same meaningsas defined above), or pharmaceutically acceptable salts thereof.

The present invention relates to UCS 1025 derivatives, wherein, informula (I), R¹ is hydrogen, NR⁹R¹⁰ (wherein R⁹ and R¹⁰ have the samemeanings as defined above), SR¹² (wherein R¹² has the same meaning asdefined above) or OR¹³ (wherein R¹³ has the same meaning as definedabove), or pharmaceutically acceptable salts thereof.

The present invention relates to UCS 1025 derivatives, wherein, informula (I), R² and R³ represent hydrogen at the same time or R² and R³are combined to represent a bond, or pharmaceutically acceptable saltsthereof. Among these, preferred examples include UCS 1025 derivatives,wherein R⁴ is hydrogen, CO₂R¹⁶ (wherein R¹⁶ has the same meaning asdefined above) or CONR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ have the same meaningsas defined above), or pharmaceutically acceptable salts; and UCS 1025derivatives, wherein R¹ is hydrogen, NR⁹R¹⁰ (wherein R⁹ and R¹⁰ have thesame meanings as defined above), SR¹² (wherein R¹² has the same meaningas defined above) or OR¹³ (wherein R¹³ has the same meaning as definedabove), or pharmaceutically acceptable salts thereof.

The present invention relates to UCS 1025 derivatives, wherein, informula (I), R⁷ and R⁸ are combined to represent ═O, or pharmaceuticallyacceptable salts thereof. Among these, preferred examples include UCS1025 derivatives, wherein R⁴ is hydrogen, CO₂R¹⁶ (wherein R¹⁶ has thesame meaning as defined above) or CONR¹⁷R¹⁰ (wherein R¹⁷ and R¹⁸ havethe same meanings as defined above), or pharmaceutically acceptablesalts thereof; UCS 1025 derivatives, wherein R¹ is hydrogen, NR⁹R¹⁰(wherein R⁹ and R¹⁰ have the same meanings as defined above), SR¹²(wherein R¹² has the same meaning as defined above) or OR¹³ (wherein R¹³has the same meaning as defined above), or pharmaceutically acceptablesalts thereof; and UCS 1025 derivatives, wherein R² and R³ representhydrogen at the same time or R² and R³ are combined to represent a bond,or pharmaceutically acceptable salts thereof.

The present invention relates to an antibacterial agent comprising, asan active ingredient, the UCS 1025 derivative represented by formula (I)or a pharmaceutically acceptable salt thereof.

The present invention relates to an antitumor agent comprising, as anactive ingredient, the UCS 1025 derivative represented by formula (I) ora pharmaceutically acceptable salt thereof.

The present invention relates to a medicament comprising, as an activeingredient, the UCS 1025 derivative represented by formula (I) or apharmaceutically acceptable salt thereof.

The present invention relates to a method for treating malignant tumors,which comprises administering a therapeutically effective amount of theUCS 1025 derivative represented by formula (I) or a pharmaceuticallyacceptable salt thereof.

The present invention relates to use of the UCS 1025 derivativerepresented by formula (I) or a pharmaceutically acceptable salt thereoffor manufacturing an antitumor agent.

Hereinafter, the compound represented by formula (I) is called Compound(I), and the same applies to the compounds of other formula numbers.

In the definition of each group of formula (I), the lower alkyl includesstraight or branched alkyl having 1 to 6 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.The lower alkanoyl includes straight or branched alkanoyl having 1 to 6carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl and the like. The lower alkenyl includes alkenylhaving 2 to 6 carbon atoms, such as vinyl, allyl, butenyl, pentenyl,hexenyl and the like, and the lower alkynyl includes alkynyl having 2 to6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyland the like. The halogen means each atom of iodine, bromine, chlorineor fluorine. Examples of the aryl include phenyl, naphthyl, pyridyl,thienyl, furyl, pyrrolyl, imidazolyl, pyrimidinyl, oxazolyl, thiazolyland the like. Examples of the heterocyclic ring formed together with theadjacent N include pyrrolidinyl, piperidino, piperazinyl, morpholino,thiomorpholino, pyrrolyl, imidazolyl, pyrazolyl and the like. The arylmoiety of the aralkyl has the same meaning as the above aryl, and thealkylene moiety of the aralkyl means a group in which one hydrogen atomis removed from the above lower alkyl.

Examples of the substituent in the substituted lower alkyl, thesubstituted lower alkenyl, the substituted lower alkynyl, thesubstituted lower alkanoyl, the substituted aryl and the substitutedaralkyl include 1 to substitutable number of, preferably 1 to 3,substituents which are the same or different, such as NR²⁰R²¹ (whereinR²⁰ and R²¹ are the same or different and each represents hydrogen,lower alkyl, aryl or aralkyl, or R²⁰ and R²¹ are combined together withthe adjacent N to form a heterocyclic ring), nitro, carboxy, CONR²²R²³(wherein R²² and R²³ are the same or different and each representshydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl,aryl or aralkyl), cyano, halogen, hydroxy, lower alkoxy, loweralkoxycarbonyl, lower alkylthio, lower alkanoyl, lower alkanoyloxy,aryl, aralkyl and the like. The lower alkyl, the lower alkenyl, thelower alkynyl, the lower alkanoyl, the aryl, the aralkyl, theheterocyclic ring formed together with the adjacent N, and the halogenhave the same meanings as defined above, respectively. The lower alkylmoieties of the lower alkoxy, the lower alkoxycarbonyl and the loweralkylthio have the same meaning as the above lower alkyl. The loweralkanoyl moiety of the lower alkanoyloxy has the same meaning as theabove lower alkanoyl.

Examples of the substituent in the substituted heterocyclic ring includearalkyloxy in addition to those exemplified as the substituent of thesubstituted lower alkyl, the substituted lower alkenyl, the substitutedlower alkynyl, the substituted lower alkanoyl and the substitutedaralkyl. The aryl moiety and the alkylene moiety of aralkyl in thearalkyloxy have the same meanings as defined above, respectively.

Examples of the pharmaceutically acceptable salts of Compound (I)include pharmaceutically acceptable acid addition salts, metal additionsalts, base addition salts and the like. Examples of thepharmaceutically acceptable acid addition salts include inorganic acidsalts such as hydrochloride, hydrobromide, sulfate, phosphate and thelike; organic acid salts such as methanesulfonate, oxalate, acetate,malonate, succinate, fumarate, maleate, tartrate, citrate and the like;and amino acid addition salts such as lysine salt, glycine salt,phenylalanine salt and the like. Examples of the pharmaceuticallyacceptable metal addition salts include alkali metal salts such assodium salt, potassium salt and the like; alkaline earth metal saltssuch as magnesium salt, calcium salt and the like; aluminum salt; zincsalt; and the like. Examples of the pharmaceutically acceptable baseaddition salts include ammonium salts such as ammonium,tetramethylammonium and the like; and addition salts of an organic aminesuch as morpholine, piperidine or the like.

Some Compounds (I) of the present invention include may exist in varietyform of an isomer such as a stereoisomer, a regio isomer, a geometricalisomer, a tautomer or the like. All of these possible isomers andmixtures thereof are included in the present invention, and the mixingratio may be any optional ratio.

Next, production methods of Compound (I) are described.

When defined groups are changed under conditions of each method orunsuitable for carrying out the method in the production methods shownbelow, the production can be easily carried out by employing methodsgenerally used in the synthetic organic chemistry, such as protectionand deprotection of functional groups (e.g., see Protective Groups inOrganic Synthesis, edited by T. W. Greene, John Wiley & Sons, Inc.(1981) and the like). Also, the order of the reaction steps such as anintroduction of the substituent and the like can be changed ifnecessary.

Production Method 1

Compound (Ia) which is Compound (I) wherein R⁴ represents CO₂R^(16a)(wherein R^(16a) represents substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, or substituted or unsubstituted aralkyl) can be producedby the following reaction step.

(wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(16a), a and ---- have thesame meanings as defined above, respectively).

Step 1:

Compound (Ia) can be produced by reacting Compound (Ib) which isCompound (I) wherein R⁴ represents carboxy, or Compound (Ic) which isCompound (I) wherein R² and R⁴ are combined to represent —O(C═O)— and R³represents hydrogen with a halide represented by R^(16a)X (whereinR^(16a) has the same meaning as defined above; and X representschlorine, bromine or iodine) in an inert solvent in the presence of anappropriate base.

The inert solvent includes ethers such as tetrahydrofuran, dioxane,etc., dimethylformamide, dichloromethane and the like. The base includessodium carbonate, sodium bicarbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide,diisopropylethylamine, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]-7-undecene and the like, which are used in anamount of 1 to 30 equivalents based on Compound (Ib) or Compound (Ic).

The halide represented by R^(16a)X (wherein R^(16a) and X have the samemeanings as defined above, respectively) is used in an amount of 1 to 30equivalents based on Compound (Ib) or Compound (Ic), and if necessary,sodium iodide or potassium iodide may be added in an amount of 1 to 30equivalents. The reaction is completed at 0° C. to the boiling point ofthe used solvent, preferably at 20 to 30° C., in 1 to 48 hours.

Compound (Ia) can also be obtained by the following method. That is, itcan be produced by reacting Compound (Ib) or Compound (Ic) with 1 to 100equivalents of a compound represented by HOR^(16a) (wherein R^(16a) hasthe same meaning as defined above) in an inert solvent in the presenceof a condensing agent.

The inert solvent is the same as the above case, and the condensingagent is not particularly limited, so long as it can be applied to thecondensation of a carboxylic acid and an alcohol. Examples thereofinclude 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide,carbonyldiimidazole, ethyl chloroformate and the like. If necessary, thereaction can be accelerated by adding 1 to 10 equivalents of a base suchas 4-dimethylaminopyridine, diisopropylethylamine, triethylamine,pyridine or the like. The reaction is completed at 0° C. to the boilingpoint of the used solvent, preferably at 20 to 30° C., generally in 0.5to 72 hours.

When Compound (Ic) is used as the starting material in the aboveproduction method, a compound which is Compound (Ia) wherein R² and R³are combined to form a bond is obtained.

Production Method 2

Compound (Id) which is Compound (I) wherein R⁴ represents CONR¹⁷R¹⁸(wherein R¹⁷ and R¹⁸ have the same meanings as defined above,respectively), or Compound (Ie) which is Compound (I) wherein R² and R⁴are combined to represent —NR¹⁴(C═O)— (wherein R¹⁴ has the same meaningas defined above) can be produced by the following reaction steps.

(wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁴, R¹⁷, R¹⁸, a and ---- havingthe same meanings as defined above, respectively).Step 2:

Compound (Id) or Compound (Ie) can be produced by reacting Compound (Ib)which is Compound (I) wherein R⁴ represents carboxy with 1 to 10equivalents of an amine represented by HNR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸have the same meanings as defined above, respectively) or an aminerepresented by H₂NR¹⁴ (wherein R¹⁴ has the same meaning as definedabove) in an inert solvent in the presence of an appropriate condensingagent.

Examples of the inert solvent include solvents similar to thosedescribed in the Production Method 1. The condensing agent is notparticularly limited, so long as it can be applied to the condensationof a carboxylic acid and an amine. Examples thereof include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide,carbonyldiimidazole, ethyl chloroformate and the like. If necessary, thereaction can be accelerated by adding 1 to 10 equivalents of a base suchas 4-dimethylaminopyridine, diisopropylethylamine, triethylamine,pyridine or the like. The reaction is completed at OC to the boilingpoint of the used solvent, preferably at 20 to 30° C., generally in 0.5to 72 hours.

Compound (Id) or Compound (Ie) can also be produced by using Compound(Ic) which is Compound (I) wherein R² and R⁴ are combined to represent—O(C═O)— and R³ represents hydrogen, as the starting material instead ofCompound (Ib), and reacting it with 1 to 10 equivalents of an aminerepresented by HNR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ have the same meanings asdefined above, respectively) or an amine represented by H₂NR¹⁴ (whereinR¹⁴ has the same meaning as defined above) in an inert solvent in thepresence of an appropriate condensing agent.

Examples of the inert solvent include solvents similar to thosedescribed in the Production Method 1. Examples of the appropriatecondensing agent include agents similar to those used in the productionof Compound (Id) or Compound (Ie) from Compound (Ib). If necessary, asin the case of the production of Compound (Id) or Compound (Ie) fromCompound (Ib), the reaction can be accelerated by adding 1 to 10equivalents of a base such as 4-dimethylaminopyridine,diisopropylethylamine, triethylamine, pyridine or the like. Also, thereaction temperature and reaction time are similar to those in theproduction of Compound (Id) or Compound (Ie) from Compound (Ib).

When Compound (Ic) is used as the starting material, a compound which isCompound (Id) wherein R² and R³ are combined to form a bond is obtained.

Production Method 3

Compound (Ifa) which is Compound (I) wherein ---- represents a singlebond and R⁵ and R⁶ are combined to represent a bond and Compound (Ifb)which is Compound (I) wherein ---- represents a double bond and R⁵ andR⁶ are combined to represent a bond can be produced by the followingreaction step.

(wherein R¹, R², R³, R⁴, R⁷, R⁸, R¹⁹ and a have the same meanings asdefined above, respectively).Step 3:

Compound (Ifa) and Compound (Ifb) can be obtained by treating Compound(Ig) which is Compound (I) wherein ---- represents a single bond, R⁵represents hydrogen and R⁶ represents OR¹⁹ (wherein R¹⁹ has the samemeaning as defined above) with an appropriate acid catalyst in an inertsolvent.

The inert solvent includes hydrocarbons such as toluene, hexane, etc.;ethers such as tetrahydrofuran, dioxane, etc.; dichloromethane;chloroform; and the like. The appropriate acid catalyst includes proticacids such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate,hydrogen chloride, hydrogen bromide, acetic acid, trifluoroacetic acidand the like, and Lewis acids such as aluminum chloride, a borontrifluoride ether complex, titanium tetrachloride and the like, whichare used in an amount of 0.1 to 10 equivalents. The reaction iscompleted at 0° C. to the boiling point of the used solvent generally in0.1 to 10 hours.

Production Method 4

Compound (Ih) which is Compound (I) wherein R³ is chlorine, bromine oriodine can be produced by the following reaction step.

(wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, a and ---- have the same meaningsas defined above, respectively; and Y represents chlorine, bromine oriodine).Step 4:

Compound (Ih) can be obtained by reacting Compound (Ii) which isCompound (I) wherein R³ represents hydrogen with 1 to 10 equivalents ofN-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide or the likein an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide,dichloromethane or the like. The reaction is completed at 0° C. to theboiling point of the used solvent, preferably at 20 to 80° C., generallyin 0.5 to 10 hours.

Production Method 5

Compound (Ij) which is Compound (I) wherein R² and R³ are combined torepresent a bond can be produced by the following reaction step.

(wherein R¹, R⁴, R⁵, R⁶, R⁷, R⁸, a and ---- have the same meanings asdefined above, respectively; and Y^(a) represents bromine or iodine).Step 5:

Compound (Ij) can be obtained by treating Compound (Iha) which isCompound (I) wherein R² represents hydrogen and Y^(a) represents bromineor iodine with 1 to 10 equivalents of a base such as potassiumtert-butoxide, diisopropylethylamine, 4-dimethylaminopyridine,1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]-7-undecene or thelike in an inert solvent such as tetrahydrofuran, dioxane,dimethylformamide, dichloromethane or the like. The reaction iscompleted at −20° C. to the boiling point of the used solvent,preferably at 0 to 30° C., generally in 0.5 to 10 hours.

Production Method 6

Compound (Ika) which is Compound (I) wherein R¹ is NR⁹R¹⁰ (wherein R⁹and R¹⁰ have the same meanings as defined above, respectively) or SR¹²(wherein R¹² has the same meaning as defined above) can be produced bythe following reaction step.

{wherein R⁴, R⁵, R⁶, R⁷, R⁸, a and ---- have the same meanings asdefined above, respectively; and R¹⁸ represents NR⁹R¹⁰ (wherein R⁹ andR¹⁰ have the same meanings as defined above, respectively) or SR¹²(wherein R¹² has the same meaning as defined above)}.Step 6:

Compound (Ika) can be obtained by reacting Compound (Ija) which isCompound (I) wherein R² and R³ are combined to represent a bond and R¹represents hydrogen with 1 to 10 equivalents of an amine represented byHNR⁹R¹⁰ (wherein R⁹ and R¹⁰ have the same meanings as defined above,respectively) or a thiol represented by HSR¹² (wherein R¹² has the samemeaning as defined above) in an inert solvent, if necessary, in thepresence of a base.

The inert solvent includes organic solvents such as dimethyl sulfoxide,dimethylformamide, tetrahydrofuran, dioxane, etc., a phosphate bufferhaving a pH value of 6 to 10, preferably 7 to 8, and the like, which areused alone or as a mixture. The base is preferably 1 to 10 equivalentsof an tertiary amine such as pyridine, 4-dimethylaminopyridine,triethylamine, diisopropylethylamine or the like. The reaction iscompleted at 0° C. to the boiling point of the used solvent, preferablyat 20 to 30° C., generally in 0.1 to 10 hours.

Production Method 7

Compound (Im) which is Compound (I) wherein a is an oxygen atom can beproduced by the following reaction step.

(wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and ---- have the same meaningsas defined above, respectively).Step 7:

Compound (In) can be obtained by treating Compound (In) which isCompound (I) wherein a represents a single bond with 1 to 10 equivalentsof an oxidizing agent in an inert solvent.

The inert solvent includes dichloromethane, chloroform, methanol,ethanol and the like, which are used alone or as a mixture. Theoxidizing agent is preferably m-chloroperbenzoic acid, dimethyldioxiraneor the like. The reaction is completed at 0° C. to the boiling point ofthe used solvent, preferably at 20 to 30° C., generally in 0.5 to 24hours.

Production Method 8

Compound (Ip) which is Compound (I) wherein R³ and/or R⁶ representsOR^(15a) (wherein R^(15a) represents substituted or unsubstituted loweralkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, or substituted or unsubstituted aralkyl)can be produced by the following reaction step.

{wherein R¹, R², R⁴, R⁵, R⁷, R⁸, a and ---- have the same meanings asdefined above, respectively; at least one of R^(3a) and R^(6a)represents OR^(15a) (wherein R^(15a) has the same meaning as definedabove; and wherein, when R^(3a) is not OR^(15a) (wherein R^(15a) has thesame meaning as defined above), R^(3a) represents a group excludingOR^(15a) (wherein R^(15a) has the same meaning as defined above) fromthe definition of R³, and when R^(6a) is not OR^(15a) (wherein R^(15a)has the same meaning as defined above), R^(6a) represents a groupexcluding OR^(15a) (wherein R^(15a) has the same meaning as definedabove) from the definition of R⁶); and at least one of R^(3b) and R^(6b)represents hydroxy (wherein, when R^(3b) is not hydroxy, R^(3b)represents a group excluding hydroxy from the definition of R³, and whenR^(6b) is not hydroxy, R^(6b) represents a group excluding hydroxy fromthe definition of R⁶)}.Step 8:

Compound (Ip) can be produced by reacting Compound (Iq) which isCompound (I) wherein R³ and/or R⁶ represents hydroxy with a haliderepresented by R^(15a)X (wherein R^(15a) and X have the same meanings asdefined above) in an inert solvent in the presence of a base.

The inert solvent includes ethers such as tetrahydrofuran, dioxane,etc.; dimethylformamide; dichloromethane; and the like. The baseincludes sodium hydride, potassium tert-butoxide, isopropylethylamine,lithium diisopropylamide and the like, which are used in an amount of 1to 5 equivalents based on Compound (Iq) as the starting material.

The halide represented by R^(15a)X (wherein R^(15a) and X have the samemeanings as defined above) is used in an amount of 1 to 10 equivalentsbased on Compound (Iq) as the starting material, and if necessary,sodium iodide or potassium iodide may be added in an amount of 1 to 10equivalents. The reaction is completed at −78° C. to the boiling pointof the used solvent, preferably at 0 to 30° C., in 1 to 48 hours.

Production Method 9

Compound (Ir) which is Compound (I) wherein R³ and/or R⁶ representsOR^(15b) (wherein R^(15b) represents substituted or unsubstituted loweralkanoyl) can be produced by the following reaction step.

{wherein R¹, R², R^(3b), R⁴, R⁵, R^(6b), R⁷, R⁸, a and ---- have thesame meanings as defined above, respectively; at least one of R^(3a) andR^(6c) represents OR^(15b) (wherein R^(15b) has the same meaning asdefined above; and wherein, when R^(3c) is not OR^(15b) (wherein R^(15b)has the same meaning as defined above), R^(3c) represents a groupexcluding OR^(15b) (wherein R^(15b) has the same meaning as definedabove) from the definition of R³, and when R^(6c) is not OR^(15b)(wherein R^(15b) has the same meaning as defined above), R^(6c)represents a group excluding OR^(15b) (wherein R^(15b) has the samemeaning as defined above) from the definition of R⁶)}.Step 9:

Compound (Ir) can be obtained by reacting Compound (Iq) which isCompound (I) wherein R³ and/or R⁶ is hydroxy with 1 to 10 equivalents ofa reactive derivative of a carboxylic acid represented by R^(15b)OH(wherein R^(15b) has the same meaning as defined above) in an inertsolvent, if necessary, in the presence of a base.

The inert solvent includes dichloromethane, chloroform,dimethylformamide and the like. The reactive derivative of a carboxylicacid includes an acid halide, an acid anhydride, a mixed acid anhydrideand the like. The base is preferably a tertiary amine such as pyridine,4-dimethylaminopyridine, triethylamine, diisopropylethylamine or thelike, which may be used as the solvent at the same time. The reaction iscompleted at 0° C. to the boiling point of the used solvent, preferablyat 20 to 30° C., in 1 to 48 hours.

Production Method 10

Compound (Is) which is Compound (I) wherein R¹ represents hydrogen, R²and R³ are combined to represent —O— and R⁴ represents CONR¹⁶ (whereinR¹⁶ has the same meaning as defined above) or CONR¹⁷R¹⁸ (wherein R¹⁷ andR¹⁸ have the same meanings as defined above, respectively) can beproduced by the following reaction step.

{wherein R⁵, R⁶, R⁷, R⁸, a and ---- have the same meanings as definedabove, respectively; R^(3a) represents bromine or iodine; and R^(4a)represents COOR¹⁶ (wherein R¹⁶ has the same meaning as defined above) orCONR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ have the same meanings as defined above,respectively)}.Step 10:

Compound (Is) can be obtained by reacting Compound (It) which isCompound (I) wherein R¹ is hydrogen, R³ is bromine or iodine and R² andR⁴ are combined to represent —O(C═O)— with 1 equivalent to a solventamount, preferably 10 equivalents or more, of water or an alcoholrepresented by HOR¹⁶ (wherein R¹⁶ has the same meaning as defined above)or an amine represented by HNR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ have the samemeanings as defined above, respectively) in an inert solvent, ifnecessary, in the presence of a base.

The inert solvent includes dichloromethane, dimethylformamide,tetrahydrofuran and the like. The alcohol includes lower alcohols suchas methanol, ethanol, allyl alcohol and the like, which may be used asthe solvent at the same time. The base includes potassium carbonate,sodium carbonate, sodium bicarbonate, sodium hydroxide, potassiumhydroxide, triethylamine, diisopropylethylamine, dimethylaminopyridineand the like, which are used in an amount of 1 to 10 equivalents. Anyprimary amine or secondary amine is used as the amine. Examples thereofinclude dialkylamines such as dimethylamine, diethylamine and the like;and cyclic amines such as morpholine, piperidine, piperazine and thelike. The reaction is completed at −20° C. to the boiling point of theused solvent, preferably at 0 to 30° C., in 1 to 48 hours.

Production Method 11

Compound (Ikb) which is Compound (I) wherein R¹ represents OR^(13a)(wherein R^(13a) represents substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, or substituted orunsubstituted lower alkynyl) can be produced by the following reactionstep.

(wherein R⁴, R⁵, R⁶, R⁷, R⁸, R^(13a), a and ---- have the same meaningsas defined above, respectively).Step 11:

Compound (Ikb) can be obtained by reacting Compound (Ija) which isCompound (I) wherein R¹ is hydrogen and R² and R³ are combined torepresent a bond with 1 equivalent to a solvent amount of a loweralcohol represented by HOR^(13a) (wherein R^(13a) has the same meaningas defined above) in an inert solvent in the presence of an acidcatalyst.

The inert solvent includes dichloromethane, chloroform,dimethylformamide, tetrahydrofuran, dioxane, toluene and the like. Theacid catalyst includes trifluoroacetic acid, p-toluenesulfonic acid andthe like, which are used in an amount of 0.01 to 10 equivalents. Thereaction is completed at 0° C. to the boiling point of the used solvent,preferably at 0 to 30° C., in 1 to 72 hours.

When Compound (Ija) wherein R⁶ is OR¹⁹ (wherein R¹⁹ has the same meaningas defined above) is used as the starting material, a compound which isCompound (Ikb) wherein R⁶ is OR^(13a) (wherein R^(13a) has the samemeaning as defined above) may be obtained.

Production Method 12

Compound (Iu) which is Compound (I) wherein R² and R³ are combined torepresent —CH═N—NH— or Compound (Iv) which is Compound (I) wherein R¹ ismethyl and R² and R³ are combined to represent a bond can be produced bythe following reaction step.

(wherein R⁴, R⁵, R⁶, R⁷, R⁸, a and ---- have the same meanings asdefined above, respectively).Step 12:

Compound (Iu) or Compound (Iv) can be obtained by treating Compound(Ija) which is Compound (I) wherein R¹ is hydrogen and R² and R³ arecombined to represent a bond, or Compound (Iw) which is Compound (I)wherein R² and R⁴ are combined to represent —O(C═O)—, R¹ representshydrogen and R³ represents hydrogen with 1 equivalent to an excessamount of diazomethane in an inert solvent.

The inert solvent includes ethers such as ether, tetrahydrofuran,dioxane and the like; and alcohols such as methanol, ethanol and thelike, which are used alone or as a mixture. The reaction is completed at−20° C. to the boiling point of the used solvent, preferably at 0 to 20°C., in 0.1 to 1 hour.

Compound (I) having a desired functional group at a desired position canbe obtained by carrying out the reaction using an optional combinationof the above methods and methods generally used in the synthetic organicchemistry.

The desired compound in each of the above production methods can beisolated and purified by subjecting it to the purification methodgenerally used in the synthetic organic chemistry, e.g., filtration,extraction, washing, drying, concentration, recrystallization, varioustypes of chromatography or the like.

When it is desirable to obtain a salt of Compound (I), Compound (I) maybe purified as such when it is obtained in the form of a salt, and whenit is obtained in the free form, it may be isolated and purified by ausual method, namely by dissolving or suspending Compound (I) in anappropriate solvent and then adding a desired acid, metal or basethereto to effect formation of the salt.

In addition, Compound (I) and a pharmaceutically acceptable salt thereofmay exist in the form of an addition product with water or varioussolvents, and these addition products are also included in the presentinvention.

Compound (I) or a pharmaceutically acceptable salt thereof can be usedas such or in various preparation forms according to its pharmacologicalactions and purposes of administration. Pharmaceutical compositions ofthe present invention can be produced by uniformly mixing Compound (I)or a pharmaceutically acceptable salt thereof, in an amount effective asthe active ingredient, with a pharmaceutically acceptable carrier. Thecarrier can take a wide variety of forms according to each preparationform desirable for the administration. It is desirable that thepharmaceutical composition is in a unit dosage form suitable for itsoral or parenteral administration such as injection or the like.

In preparing tablets, for example, fillers such as lactose, glucose,sucrose, mannitol, methyl cellulose or the like; disintegrators such asstarch, sodium alginate, carboxymethyl cellulose calcium, crystallinecellulose or the like; lubricants such as magnesium stearate, talc orthe like; binders such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose or the like;surfactants such as a sucrose fatty acid ester, a sorbitol fatty acidester or the like; or the like may be used in accordance with the usualmethod. Tablets containing 1 to 300 mg of the active ingredient per onetablet are preferable.

In preparing granules, for example, fillers such as lactose, sucrose orthe like, disintegrators such as starch or the like, binders such asgelatin or the like, or the like may be used in the usual way. Inpreparing powders, for example, fillers such as lactose, mannitol or thelike, or the like may be used in accordance with the usual method. Inpreparing capsules, for example, gelatin, water, sucrose, acacia,sorbitol, glycerol, crystalline cellulose, magnesium stearate, talc orthe like may be used in the usual way. Capsules containing 1 to 300 mgof the active ingredient per one capsule are preferable.

In preparing injections, solvents such as water, physiological saline,plant oil (e.g., olive oil, peanut oil or the like), ethyl oleate,propylene glycol or the like; solubilizing agents such as sodiumbenzoate, sodium salicylate, urethane or the like; isotonicity agentssuch as sodium chloride, glucose or the like; preservatives such asphenol, cresol, a p-hydroxybenzoic acid ester, chlorobutanol or thelike; antioxidants such as ascorbic acid, sodium pyrosulfite or thelike; or the like may be used in the usual way.

Compound (I) or a pharmaceutically acceptable salt thereof can beadministered by an oral method or a parenteral method using injectionsor the like. Although its effective dose and administration frequencyvary depending on the administration form, the age or body weight of thepatient, symptoms of the disease and the like, it is generallypreferable to administer it 1 to 4 times per day at a dose of 0.01 to 20mg/kg per day.

Examples of Compound (I) obtained by the present invention are shown inthe following Table 1 (1) to Table 1 (9), although the scope of thepresent invention is not limited to these compounds.

TABLE 1 Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

Next, biological activities of specific Compounds (I) are describedbased on test examples.

TEST EXAMPLE 1

Antibacterial Activity:

Antibacterial activities (minimum inhibitory concentration (MIC: mg/ml))of Compounds (I) on various bacteria are shown in Table 2. Theantibacterial activity was measured by an agar dilution method using amedium comprising 3 g/L Bacto-Tryptone (manufactured by Difco), 3 g/Lmeat extract, 1 g/L yeast extract, 1 g/L glucose and 16 g/L agar.

TABLE 2 Compound No. ER¹ SA² BS³ 1 0.52 1.0 0.52 6 3.6 3.6 1.8 7 5.0 101.3 8 1.5 12 0.38 32 13 53 13 36 48 95 48 38 8.1 33 16 ¹ Enteroccccushirae ATCC 10541 ² Staphylococcus aureus ATCC 6538P ³ Bacillus subtilisATCC 10707

TEST EXAMPLE 2

Growth Inhibition Action on Human Renal Carcinoma Cell Line ACHN:

Cells of human renal carcinoma cell line ACHN adjusted to a density of3×10⁴ cells/ml with RPMI (Roswell Park Memorial Institute) mediumcomprising 10% fetal bovine serum and 2 mmol/l glutamine were dispensedin a volume of 50 μl into each well of a 96 well microtiter plate andcultured at 37° C. for 24 hours in a carbon dioxide incubator. Each ofthe test compounds serially diluted with the above medium was added toeach well in a volume of 50 μl, following by culturing at 37° C. for 72hours in a carbon dioxide incubator. After discarding the culturesupernatant, each well was washed twice with 0.1 ml of phosphatebuffered saline (PBS), and then 0.1 ml of the above medium was againadded to each well. Cell proliferation kit II (Boehringer Mannheim) wasused for the measurement of the number of cells in each well. Afteraddition of a color-producing reagent and subsequent incubation at 37°C. for 3 hours in a carbon dioxide incubator, absorbance at 490 nm and655 nm was measured using a microplate reader, and a value (differentialabsorbance) was calculated by subtracting the absorbance at 655 nm fromthe absorbance at 490 nm in each well. By comparing the differentialabsorbance obtained from untreated cells and that obtained from cellstreated with a predetermined concentration of each test compound, theconcentration of the test compound capable of inhibiting 50% of the cellgrowth was calculated and expressed as IC₅₀. The results are shown inTable 3.

TABLE 3 Compound No. IC₅₀ (μM) 1 4.4 6 5.6 8 2.7 12 5.7 16 64

According to Table 2 and Table 3, Compound (I) has excellent antitumoractivity and is useful as a therapeutic agent for malignant tumors. Itis also useful as an antibacterial agent.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples are shown in the following. Physicochemical data of eachcompound in the following examples were measured using the followinginstruments.

¹H NMR: Bruker DMX 500 (500 MHz) JEOL Alpha 400 (400 MHz) JEOL Lambda300 (300 MHz).

FABMS JEOL JMS-HX110.

In the following examples, UCS 1025A represented by the followingformula (Xa) and UCS 1025B represented by the following formula (Xb)were used as the starting materials.

EXAMPLE 1 Compound 1

UCS 1025A (100 mg, 0.280 mmol) was dissolved in dimethylformamide (6ml), and sodium carbonate (30 mg, 0.28 mmol) and iodomethane (0.52 ml,8.4 mmol) were added thereto, followed by stirring at room temperaturefor 18 hours. Water was added to the reacting mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine and then dried over anhydrous sodium sulfate.The solvent was evaporated under a reduced pressure, and the resultingresidue was purified by silica gel column chromatography(2:1=hexane:ethyl acetate) to obtain Compound 1 (39 mg, 37%).

¹H NMR (500 MHz, CDCl₃) δ 0.79 (d, J=7.1 Hz, 3H), 0.85 (m, 1H), 1.10 (m,1H), 1.2-1.9 (m, 8H), 2.5-2.6 (m, 2H), 2.71 (ddt, J=6.8, 13.2, 9.0 Hz,1H), 3.18 (d, J=6.8 Hz, 1H), 3.35 (ddd, J=11.0, 9.0, 2.9 Hz, 1H), 3.52(dd, J=11.3, 5.7 Hz, 1H), 3.59 (s, 3H), 3.79 (dt, J=11.0, 9.0 Hz, 1H),5.39 (d, J=9.8 Hz, 1H), 5.53 (ddd, J=9.8, 4.6, 2.5 Hz, 1H), 7.48 (s,1H).

FABMS m/z 374 (M+H)⁺ C₂₁H₂₇NO₅=373.

EXAMPLE 2 Compound 2

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dimethylformamide (2 ml),and sodium carbonate (6.0 mg, 0.056 mmol) and benzyl bromide (0.020 ml,0.17 mmol) were added thereto, followed by stirring at room temperaturefor 1 hour. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated over a reduced pressure, and the resultingresidue was purified by silica gel column chromatography(1:1=hexane:ethyl acetate) to obtain Compound 2 (17 mg, 68%).

¹H NMR (300 MHz, CDCl₃) δ 0.78 (d, J=7.2 Hz, 3H), 1.0-1.9 (m, 10H),2.5-2.8 (m, 4H), 3.28 (dd, J=7.1, 2.1 Hz, 1H), 3.35 (m, 1H), 3.54 (dd,J=11.2, 5.7 Hz, 1H), 3.80 (dt, J=11.2, 8.6 Hz, 1H), 4.95 (d, J=12.1 Hz,1H), 5.00 (d, J=12.3 Hz, 1H), 5.39 (br d, J=9.9 Hz, 1H), 5.53 (ddd,J=9.7, 4.4, 2.6 Hz, 1H), 7.3-7.4 (m, 5H), 7.49 (s, 1H).

FABMS m/z 450 (M+H)⁺ C₂₇H₃₁NO₅=449.

EXAMPLE 3 Compounds 3 and 45

UCS 1025A (200 mg, 0.557 mmol) was dissolved in dimethylformamide (10ml), and 2-chloro-1-methylpyridinium iodide (711 mg, 2.79 mmol) wasadded thereto, followed by stirring at room temperature for 35 minutes.A methanol solution of ammonia (about 6.8 mol/L, 0.82 ml, 5.6 mmol) wasadded thereto, followed by stirring at room temperature for 25 minutes.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was recrystallized from ethyl acetate to obtain Compound 3 (85mg, 43%). The mother liquor was concentrated and the residue waspurified by preparative thin layer chromatography(9:1=chloroform:methanol) to obtain Compound 3 (12 mg, 6%) and Compound45 (39 mg, 20%).

Compound 3:

¹H NMR (300 MHz, CDCl₃) δ 0.66 (d, J=7.2 Hz, 3H), 0.7-1.5 (m, 5H),1.6-1.9 (m, 5H), 2.23 (m, 1H), 2.4-2.5 (m, 2H), 2.93 (d, J=5.9 Hz, 1H),3.12 (m, 1H), 3.4-3.6 (m, 2H), 5.37 (d, J=9.9 Hz, 1H), 5.54 (ddd, J=9.7,4.2, 2.4 Hz, 1H), 6.54 (s, 1H), 6.96 (br s, 1H), 7.52 (br s, 1H), 7.59(s, 1H).

FABMS m/z 359 (M+H)⁺ C₂₀H₂₆N₂O₄=358.

Compound 45:

¹H NMR (300 MHz, CDCl₃) δ 0.78 (d, J=7.0 Hz, 3H), 0.8-1.8 (m, 10H),2.4-2.7 (m, 2H), 2.92 (m, 1H), 3.05 (dd, J=9.2, 2.4 Hz, 1H), 3.13 (dd,J=11.2, 5.5 Hz, 1H), 3.33 (ddd, J=11.9., 9.7, 5.5 Hz, 1H), 3.81 (m, 1H),3.82 (s, 1H), 4.04 (s, 1H), 4.82 (s, 1H), 5.40 (d, J=9.9 Hz, 1H), 5.59(ddd, J=9.9, 4.8, 2.4 Hz, 1H), 6.61 (br s, 1H).

FABMS m/z 359 (M+H)⁺ C₂₀H₂₆N₂O₄=358.

EXAMPLE 4 Compound 4

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (5 ml),and 2-chloro-1-methylpyridinium iodide (42 mg, 0.17 mmol) andpropylamine (0.014 ml, 0.17 mmol) were added thereto, followed bystirring at room temperature for 45 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate) to obtain Compound 4 (10 mg, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.78 (d, J=7.2 Hz, 3H), 0.88 (t, J=7.4 Hz,3H), 1.0-1.9 (m, 12H), 2.3-2.7 (m, 3H), 2.94 (dd, J=7.0, 2.6 Hz, 1H),3.0-3.3 (m, 3H), 3.32 (m, 1H), 3.56 (dd, J=11.0, 5.1 Hz, 1H), 3.89 (dt,J=11.2, 8.1 Hz, 1H), 5.38 (br d, J=9.7 Hz, 1H), 5.53 (ddd, J=9.9, 4.4,2.5 Hz, 1H), 5.86 (br s, 1H), 7.46 (s, 1H).

FABMS m/z 401 (M+H)⁺ C₂₃H₃₂N₂O₄=400.

EXAMPLE 5 Compound 5

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (5 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) anddimethylamine (a 2 mol/L tetrahydrofuran solution, 0.14 ml, 0.28 mmol)were added thereto, followed by stirring at room temperature for 1 hour.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by preparative thin layer chromatography (ethylacetate) to obtain Compound 5 (5.2 mg, 24%).

¹H NMR (300 MHz, CDCl₃) δ 0.78 (d, J=7.2 Hz, 3H), 1.0-2.0 (m, 10H),2.4-2.7 (m, 3H), 2.85 (S, 3H), 3.16 (S, 3H), 3.30 (m, 1H), 3.44 (dd,J=11.2, 5.7 Hz, 1H), 3.5-3.6 (m, 2H), 3.89 (m, 1H), 5.38 (d, J=9.7 Hz,1H), 5.51 (m, 1H), 7.30 (S, 1H).

FABMS m/z 387 (M+H)⁺ C₂₂H₃₀N₂O₄=386.

EXAMPLE 6 Compound 6

UCS 1025A (120 mg, 0.334 mmol) was dissolved in dichloromethane (20 ml),and 2-chloro-1-methylpyridinium iodide (426 mg, 1.67 mmol) was addedthereto, followed by stirring at room temperature for 20 minutes. Then,diethylamine (0.173 ml, 1.67 mmol) was added thereto, followed bystirring at room temperature for 20 minutes. Water was added thereto andthe mixture was extracted with chloroform. The organic layer was washedwith saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by silica gel column chromatography(2:3=hexane:ethyl acetate) to obtain Compound 6 (100 mg, 70%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (d, J=7.3 Hz, 3H), 0.80 (m, 1H), 0.99 (t,J=7.1 Hz, 3H), 1.16 (m, 1H), 1.22 (t, J=7.1 Hz, 3H), 1.31 (m, 2H), 1.50(m, 1H), 1.6-1.9 (m, 5H), 2.4-2.7 (m, 3H), 2.62 (s, 1H), 2.98 (m, 1H),3.2-3.4 (m, 2H), 3.40 (dd, J=7.1, 2.7 Hz, 1H), 3.57 (m, 2H), 3.65 (dd,J=11.2, 5.6 Hz, 1H), 3.94 (dt, J=10.5, 8.1 Hz, 1H), 5.38 (br d, J=9.5Hz, 1H), 5.52 (ddd, J=9.8, 4.6, 2.7 Hz, 1H), 7.36 (s, 1H).

FABMS m/z 415 (M+H)⁺ C₂₄H₃₄N₂O₄=414.

EXAMPLE 7 Compound 7

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) anddipropylamine (0.038 ml, 0.28 mmol) were added thereto, followed bystirring at room temperature for 35 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by preparative thinlayer chromatography (7:1=chloroform:acetonitrile) to obtain Compound 7(16 mg, 65%).

¹H NMR (400 MHz, CDCl₃) δ 0.77 (d, J=7.2 Hz, 3H), 0.81 (t, J=7.3 Hz,3H), 0.96 (t, J=7.3 Hz, 3H), 1.0-1.9 (m, 14H), 2.4-3.0 (m, 4H), 3.1-3.7(m, 6H), 3.93 (m, 1H), 5.37 (d, J=9.5 Hz, 1H), 5.53 (ddd, J=9.5, 4.4,2.4 Hz, 1H), 7.36 (s, 1H).

FABMS m/z 443 (M+H)⁺ C₂₆H₃₈N₂O₄=442.

EXAMPLE 8 Compound 8

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) anddibutylamine (0.047 ml, 0.28 mmol) were added thereto, followed bystirring at room temperature for 15 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by preparative thinlayer chromatography (7:1=chloroform:acetonitrile) to obtain Compound 8(16 mg, 61%).

¹H NMR (400 MHz, CDCl₃) δ 0.76 (d, J=7.2 Hz, 3H), 0.88 (t, J=7.3 Hz,3H), 0.98 (t, J=7.3 Hz, 3H), 1.0-2.0 (m, 18H), 2.4-2.7 (m, 3H), 2.87 (m,1H), 3.1-3.6 (m, 6H), 3.89 (m, 1H), 5.37 (d, J=9.9 Hz, 1H), 5.52 (m,1H), 7.29 (s, 1H).

FABMS m/z 471 (M+H)⁺ C₂₈H₄₂N₂O₄=470.

EXAMPLE 9 Compound 9

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) andN-methylbutylamine (0.029 ml, 0.28 mmol) were added thereto, followed bystirring at room temperature for 4 hours. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by preparative thinlayer chromatography (7:1=chloroform:acetonitrile) to obtain Compound 9(7.6 mg, 33%).

¹H NMR (main rotational isomer) (400 MHz, CDCl₃) δ 0.77 (d, J=7.0 Hz,3H), 0.82 (t, J=7.3 Hz, 3H), 1.0-1.9 (m, 12H), 2.4-2.7 (m, 3H), 3.0-4.0(m, 6H), 3.13 (s, 3H), 5.37 (d, J=9.7 Hz, 1H), 5.52 (ddd, J=9.7, 4.6,2.4 Hz, 1H), 7.34 (s, 1H).

FABMS m/z 415 (M+H)⁺ C₂₄H₃₄N₂O₄=414.

EXAMPLE 10 Compound 10

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) andN-methylbenzylamine (0.036 ml, 0.28 mmol) were added thereto, followedby stirring at room temperature for 19 hours. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by preparative thinlayer chromatography (7:1=chloroform:acetonitrile) to obtain Compound 10(7.0 mg, 27%).

¹H NMR (main rotational isomer) (400 MHz, CDCl₃) δ 0.78 (d, J=7.0 Hz,3H), 1.0-2.0 (m, 10H), 2.4-2.7 (m, 3H), 3.05 (s, 3H), 3.2-4.0 (m, 4H),4.42 (d, J=14.3 Hz, 1H), 4.57 (d, J=14.3 Hz, 1H), 5.39 (d, J=9.5 Hz,1H), 5.60 (m, 1H), 7.1-7.5 (m, 5H), 7.29 (s, 1H).

FABMS m/z 463 (M+H)⁺ C₂₈H₃₄N₂04=462.

EXAMPLE 11 Compound 11

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (71 mg, 0.28 mmol) and piperidine(0.028 ml, 0.28 mmol) were added thereto, followed by stirring at roomtemperature for 18 hours. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and then dried over anhydrous sodiumsulfate. The solvent was evaporated under a reduced pressure, and theresulting residue was purified by preparative thin layer chromatography(1:2=hexane:ethyl acetate) to obtain Compound 11 (5.7 mg, 24%).

¹H NMR (300 MHz, CDCl₃) δ 0.77 (d, J=7.2 Hz, 3H), 1.0-2.0 (m, 16H),2.4-2.7 (m, 3H), 3.2-3.7 (m, 8H), 3.87 (m, 1H), 5.37 (d, J=9.9 Hz, 1H),5.52 (ddd, J=9.7, 4.6, 2.6 Hz, 1H), 7.31 (s, 1H).

FABMS m/z 427 (M+H)⁺ C₂₅H₃₄N₂O₄=426.

EXAMPLE 12 Compound 12

Compound 6 (17 mg, 0.041 mmol) was dissolved in dimethyl sulfoxide (3ml), and a potassium phosphate buffer (10 mmol/L, pH=7.0, 12 ml) andethanethiol (0.0060 ml, 0.082 mmol) were added thereto, followed bystirring at room temperature for 1 hour. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and then dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure, andthe resulting residue was triturated with hexane to obtain Compound 12(12 mg, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.82 (d, J=7.1 Hz, 3H), 0.9-2.0 (m, 10H), 1.18(t, J=7.1 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.4 Hz, 3H), 2.18(m, 1H), 2.5-2.7 (m, 3H), 3.17 (dd, J=7.5, 2.0 Hz, 1H), 3.2-3.3 (m, 3H),3.5-3.6 (m, 3H), 3.59 (dd, J=11.3, 5.8 Hz, 1H), 3.7-3.8 (m, 1H), 3.77(d, J=9.7 Hz, 1H), 4.09 (s, 1H), 4.41 (d, J=9.7 Hz, 1H), 5.41 (d, J=9.7Hz, 1H), 5.54 (ddd, J=9.8, 4.6, 2.7 Hz, 1H).

FABMS m/z 477 (M+H)⁺ C₂₆H₄₀N₂O₄S=476.

EXAMPLE 13 Compound 13

Compound 6 (15 mg, 0.036 mmol) was dissolved in dimethyl sulfoxide (1ml), and a potassium phosphate buffer (10 mmol/L, pH=7.0, 0.5 ml) and2-propanethiol (0.0067 ml, 0.072 mmol) were added thereto, followed bystirring at room temperature for 15 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (2:3=hexane:ethyl acetate) to obtain Compound 13(14 mg, 79%).

¹H NMR (300 MHz, CDCl₃) δ 0.81 (d, J=7.0 Hz, 3H), 1.0-2.1 (m, 10H), 1.18(t, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.26 (t, J=6.8 Hz, 3H), 1.32(t, J=6.6 Hz, 3H), 2.5-2.7 (m, 2H), 2.89 (m, 1H), 3.1-3.8 (m, 9H), 3.74(d, J=9.5 Hz, 1H), 4.42 (s, 1H), 4.54 (d, J=9.5 Hz, 1H), 5.40 (d, J=9.5Hz, 1H), 5.55 (ddd, J=9.7, 4.5, 2.7 Hz, 1H).

FABMS m/z 491 (M+H)⁺ C₂₇H₄₂N₂O₄S=490.

EXAMPLE 14 Compound 14

Compound 6 (15 mg, 0.036 mmol) was dissolved in dimethyl sulfoxide (1ml), and a potassium phosphate buffer (10 mmol/L, pH=7.0, 0.5 ml) andthiophenol (0.0074 ml, 0.072 mmol) were added thereto, followed bystirring at room temperature for 35 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by preparativethin layer chromatography (1:2=hexane:ethyl acetate) to obtain Compound14 (12 mg, 64%).

¹H NMR (300 MHz, CDCl₃) δ 0.83 (t, J=7.2 Hz, 3H), 0.84 (d, J=7.0 Hz,3H), 1.0-2.2 (m, 10H), 1.04 (t, J=7.2 Hz, 3H), 2.5-3.4 (m, 9H), 3.62(dd, J=11.2, 5.7 Hz, 1H), 3.73 (m, 1H), 3.91 (d, J=9.9 Hz, 1H), 4.35 (s,1H), 4.83 (d, J=9.9 Hz, 1H), 5.42 (d, J=9.9 Hz, 1H), 5.56 (ddd, J=9.9,4.4, 2.6 Hz, 1H), 7.3-7.4 (m, 3H), 7.6-7.7 (m, 2H).

FABMS m/z 525 (M+H)⁺ C₃₀H₄₀N₂O₄S=524.

EXAMPLE 15 Compound 15

Compound 6 (18 mg, 0.043 mmol) was dissolved in ethanol (3 ml), andhydroxylamine hydrochloride (30 mg, 0.43 mmol) and pyridine (36 ml) wereadded thereto, followed by stirring at room temperature for 30 minutes.An aqueous citric acid solution was added to the reaction mixture, andthe mixture was extracted with ether. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was triturated with hexane to obtain Compound 15 (7.0 mg, 34%).

¹H NMR (300 MHz, CDCl₃) δ 0.76 (d, J=7.0 Hz, 3H), 0.9-2.0 (m, 10H), 1.16(t, J=7.0 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H), 2.1-2.7 (m, 3H), 3.1-3.9 (m,9H), 4.26 (d, J=9.4 Hz, 1H), 5.41 (d, J=9.7 Hz, 1H), 5.5-5.6 (m, 1H).

FABMS m/z 448 (M+H)⁺ C₂₄H₃₇N₃O₅=447.

EXAMPLE 16 Compounds 16 and 17

UCS 1025A (40 mg, 0.11 mmol) was dissolved in toluene (8 ml), andp-toluenesulfonic acid (4.0 mg, 0.021 mmol) was added thereto, followedby heating under reflux for 1 hour. The reaction mixture was cooled toroom temperature, an aqueous sodium bicarbonate solution was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and then dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure, andthe resulting residue was purified by silica gel column chromatography(9:1=hexane:ethyl acetate) to obtain Compound 16 (51 mg, 15%). Theaqueous layer obtained above was adjusted to pH 7 by adding 1 mol/Lhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfateand then the solvent was evaporated under a reduced pressure to obtainCompound 17 (246 mg, 65%).

Compound 16 (Enol Form):

¹H NMR (300 MHz, CDCl₃) δ 1.06 (d, J=7.0 Hz, 3H), 1.1-2.0 (m, 10H), 2.46(m, 1H), 2.53 (dd, J=11.0, 5.9 Hz, 1H), 3.51 (s, 2H), 5.43 (d, J=9.7 Hz,1H), 5.5-5.6 (m, 1H), 6.00 (m, 1H), 6.44 (t, J=3.1 Hz, 1H), 7.10 (d,J=2.9 Hz, 1H), 11.6 (br S, 1H).

FABMS m/z 298 (M+H)⁺ C₁₉H₂₃NO_(2=297.)

Compound 17 (Enol Form):

¹H NMR (300 MHz, CDCl₃) δ 0.8-2.0 (m, 10H), 1.06 (d, J=7.0 Hz, 3H), 2.47(m, 1H), 2.59 (dd, J=11.2, 5.9 Hz, 1H), 3.79 (s, 2H), 5.44 (d, J=9.5 Hz,1H), 5.5-5.6 (m, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.11 (d, J=3.1 Hz, 1H),11.4 (br s, 1H).

FABMS m/z 342 (M+H)⁺ C₂₀H₂₃NO₄=341.

EXAMPLE 17 Compound 18

Compound 17 (6.7 mg, 0.020 mmol) was dissolved in methanol (2 ml), onedrop of sulfuric acid was added thereto, followed by heating underreflux for 5 hours. The reaction mixture was cooled to room temperature,an aqueous sodium bicarbonate solution was added thereto, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine and then dried over anhydrous sodiumsulfate. The solvent was evaporated under a reduced pressure to obtainCompound 18 (6.9 mg, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.0-2.0 (m, 1H), 1.06 (d, J=7.2 Hz, 3H), 2.48(m, 1H), 2.60 (dd, J=11.2, 5.9 Hz, 1H), 3.85 (s, 5H), 5.45 (d, J=9.9 Hz,1H), 5.58 (ddd, J=9.9, 4.4, 2.6 Hz, 1H), 6.79 (d, J=3.3 Hz, 1H), 7.08(d, J=3.3 Hz, 1H), 11.4 (br s, 1H).

FABMS m/z 356 (M+H)⁺ C₂₁H₂₅NO₄=355.

EXAMPLE 18 Compound 19

Compound 17 (30 mg, 0.088 mmol) was dissolved in dichloromethane (7 ml),and 2-chloro-1-methylpyridinium iodide (111 mg, 0.44 mmol) was addedthereto, followed by stirring at room temperature for 20 minutes. Then,diethylamine (0.045 ml, 0.44 mmol) was added thereto, followed bystirring at room temperature for 10 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by silica gel columnchromatography (2:1=hexane:ethyl acetate) to obtain Compound 19 (29 mg,83%).

¹H NMR (300 MHz, CDCl₃) δ 1.0-2.0 (m, 10H), 1.04 (d, J=7.2 Hz, 3H), 1.24(t, J=7.0 Hz, 6H), 2.45 (m, 1H), 2.59 (dd, J=11.2, 5.9 Hz, 1H), 3.52 (q,J=7.0 Hz, 4H), 3.75 (s, 2H), 5.41 (d, J=10.1 Hz, 1H), 5.5-5.6 (m, 1H),6.52 (d, J=3.3 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H), 11.3 (br s, 1H).

FABMS m/z 397 (M+H)⁺ C₂₄H₃₂N₂O₃=396.

EXAMPLE 19 Compound 20

Compound 17 (10 mg, 0.029 mmol) was dissolved in tetrahydrofuran (3 ml),and N-bromosuccinimide (6.0 mg, 0.035 mmol) was added thereto, followedby stirring at room temperature for 10 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure toobtain Compound 20 (12 mg, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.72 (d, J=7.2 Hz, 1.5H), 0.8-1.9 (m, 10H),0.91 (t, J=7.2 Hz, 1.5H), 2.60 (m, 0.5H), 2.88 (m, 0.5H), 3.57 (d,J=19.3 Hz, 0.5H), 3.65 (d, J=19.4 Hz, 0.5H), 3.70 (dd, J=11.8, 5.8 Hz,0.5H), 3.74 (dd, J=11.5, 5.8 Hz, 0.5H), 4.37 (d, J=19.4 Hz, 0.5H), 4.56(d, J=19.3 Hz, 0.5H), 5.42 (d, J=9.9 Hz, 1H), 5.5-5.6 (m, 1H), 6.91 (d,J=3.3 Hz, 1H), 7.06 (d, J=3.5 Hz, 0.5H), 7.09 (d, J=3.3 Hz, 0.5H).

FABMS m/z 422, 420 (M+H)⁺ C₂₀H₂₂ ⁷⁹BrNO₄=419.

EXAMPLE 20 Compound 21

Compound 20 (12 mg, 0.029 mmol) was dissolved in tetrahydrofuran (3 ml),and 1,8-diazabicyclo[5.4.0]-7-undecene (0.0095 ml, 0.064 mmol) was addedthereto, followed by stirring at room temperature for 1 hour. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by preparativethin layer chromatography (9:1=chloroform:methanol) to obtain Compound21 (6.1 mg, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.82 (d, J=7.0 Hz, 3H), 1.0-2.0 (m, 10H), 2.60(m, 1H), 3.50 (m, 1H), 5.43 (d, J=9.7 Hz, 1H), 5.56 (m, 1H), 6.56 (br s,1H), 7.00 (br s, 1H), 8.14 (s, 1H).

FABMS m/z 340 (M+H)⁺ C₂₀H₂₁NO₄=339.

EXAMPLE 21 Compound 22

Compound 18 (20 mg, 0.056 mmol) was dissolved in tetrahydrofuran (4 ml),and N-bromosuccinimide (11 mg, 0.062 mmol) was added thereto, followedby stirring at room temperature for 10 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure toobtain a brominated product of Compound 18 (23 mg, 95%).

The brominated product of compound 18 (23 mg, 0.053 mmol) obtained abovewas dissolved in tetrahydrofuran (4 ml), and1,8-diazabicyclo[5.4.0]-7-undecene (0.013 ml, 0.085 mmol) was addedthereto, followed by stirring at room temperature for 20 minutes. Waterwas added thereto, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (6:1=hexane:ethyl acetate) to obtain Compound 22(10 mg, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.82 (d, J=7.2 Hz, 3H), 0.9-2.0 (m, 10H), 2.59(m, 1H), 3.51 (dd, J=11.2, 5.9 Hz, 1H), 3.88 (s, 3H), 5.43 (d, J=9.7 Hz,1H), 5.57 (ddd, J=9.7, 4.4, 2.4 Hz, 1H), 6.53 (d, J=3.3 Hz, 1H), 6.98(d, J=3.1 Hz, 1H), 8.11 (S, 1H).

FABMS m/z 354 (M+H)⁺ C₂₁H₂₃NO₄=353.

EXAMPLE 22 Compound 23

Compound 19 (29 mg, 0.073 mol) was dissolved in tetrahydrofuran (4 ml),and N-bromosuccinimide (16 mg, 0.088 mmol) was added thereto, followedby stirring at room temperature for 10 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure, andthe resulting residue was purified by preparative thin layerchromatography (2:1=hexane:ethyl acetate) to obtain a brominated productof Compound 19 (20 mg, 58%).

The brominated product of Compound 19 (20 mg, 0.056 mmol) obtained abovewas dissolved in tetrahydrofuran (4 ml), and1,8-diazabicyclo[5.4.0]-7-undecene (0.010 ml, 0.067 mmol) was addedthereto, followed by stirring at room temperature for 30 minutes. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine and then dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure, and the resulting residue waspurified by silica gel column chromatography (4:1=hexane:ethyl acetate)to obtain Compound 23 (8.7 mg, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.81 (d, J=7.2 Hz, 3H), 1.0-2.0 (m, 10H), 1.22(t, J=7.2 Hz, 6H), 2.58 (m, 1H), 3.4-3.6 (m, 5H), 5.41 (d, J=9.9 Hz,1H), 5.56 (ddd, J=9.7, 4.4, 2.6 Hz, 1H), 6.22 (d, J=3.1 Hz, 1H), 7.00(d, J=3.1 Hz, 1H), 8.02 (s, 1H).

FABMS m/z 395 (M+H)C₂₄H₃₀N₂O₃=394.

EXAMPLE 23 Compound 24

Compound 1 (20 mg, 0.054 mmol) was dissolved in dichloromethane (4 ml),and acetic anhydride (0.025 ml, 0.27 mmol) and 4-dimethylaminopyridine(1.3 mg, 0.011 mmol) were added thereto, followed by stirring at roomtemperature for 35 minutes. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by preparative thin layer chromatography(3:2=hexane:ethyl acetate) to obtain Compound 24 (15 mg, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.79 (d, J=7.2 Hz, 3H), 1.0-2.0 (m, 10H), 2.65(m, 1H), 3.34 (t, J=7.5 Hz, 2H), 3.77 (dd, J=11.2, 5.7 Hz, 1H), 3.85 (s,3H), 3.88 (t, J=7.5 Hz, 2H), 5.41 (d, J=9.9 Hz, 1H), 5.56 (ddd, J=9.7,4.6, 2.6 Hz, 1H), 7.86 (s, 1H).

FABMS m/z 356 (M+H)⁺ C₂₁H₂₅NO₄=355.

EXAMPLE 24 Compound 25

Compound 6 (15 mg, 0.036 mmol) was dissolved in dichloromethane (4 ml),and acetic anhydride (0.017 ml, 0.18 mmol) and 4-dimethylaminopyridine(1.0 mg, 0.0082 mmol) were added thereto, followed by stirring at roomtemperature for 1 hour. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by preparative thin layer chromatography (ethylacetate) to obtain Compound 25 (10 mg, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.77 (d, J=7.2 Hz, 3H), 1.0-2.0 (m, 10H), 1.21(t, J=7.1 Hz, 6H), 2.68 (m, 1H), 3.4-3.5 (m, 6H), 3.84 (dd, J=11.2, 5.7Hz, 1H), 3.90 (t, J=7.4 Hz, 2H), 5.40 (d, J=9.7 Hz, 1H), 5.56 (m, 1H),7.57 (s, 1H).

FABMS m/z 397 (M+H)⁺ C₂₄H₃₂N₂O₃=396.

EXAMPLE 25 Compound 26

Compound 3 (10 mg, 0.028 mmol) was dissolved in dimethyl sulfoxide (1ml), and ethanethiol (0.024 ml, 0.34 mmol) and triethylamine (0.0040 ml,0.028 mmol) were added thereto, followed by stirring at room temperaturefor 1 hour. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was triturated with hexane to obtain Compound 26 (4.9 mg, 42%).

¹H NMR (300 MHz, CDCl₃) δ 0.75 (d, J=7.0 Hz, 3H), 0.9-2.1 (m, 10H), 1.14(t, J=7.4 Hz, 3H), 2.4-2.7 (m, 5H), 2.81 (br d, J=5.9 Hz, 1H), 3.07 (m,1H), 3.28 (dd, J=13.6, 5.7 Hz, 1H), 3.43 (m, 1H), 4.07 (d, J=10.6 Hz,1H), 4.22 (d, J=10.5 Hz, 1H), 5.38 (d, J=9.7 Hz, 1H), 5.59 (ddd, J=9.7,4.2, 2.2 Hz, 1H), 6.02 (s, 1H), 7.12 (br s, 1H), 7.62 (br s, 1H).

FABMS m/z 421 (M+H)⁺ C₂₂H₃₂N₂O₄S 420.

EXAMPLE 26 Compound 27

Compound 6 (21 mg, 0.050 mmol) was dissolved in dichloromethane (2 ml),and methanol (1 ml) and trifluoroacetic acid (0.004 ml, 0.05 mmol) wereadded thereto, followed by stirring at room temperature for 23 hours.The reaction mixture was evaporated under a reduced pressure and theresulting residue was purified by preparative thin layer chromatography(9:1=chloroform:acetonitrile) to obtain Compound 27 (11 mg, 48%).

¹H NMR (400 MHz, CDCl₃) δ 0.79 (d, J=7.2 Hz, 3H), 0.9-1.9 (m, 10H), 1.22(t, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 2.2-2.4 (m, 2H), 2.60 (m,1H), 3.0-3.3 (m, 3H), 3.30 (dd, J=7.2, 3.3 Hz, 1H), 3.35 (s, 3H), 3.39(S, 3H), 3.56 (dd, J=11.2, 5.7 Hz, 1H), 3.62 (m, 2H), 3.8-3.9 (m, 2H),4.56 (d, J=8.4 Hz, 1H), 5.41 (d, J=9.7 Hz, 1H), 5.56 (ddd, J=9.7, 4.6,2.6 Hz, 1H).

FABMS m/z 461 (M+H)⁺ C₂₆H₄₀N₂O₅=460.

EXAMPLE 27 Compounds 28 and 29

UCS 1025A (54 mg, 0.15 mmol) was dissolved in dichloromethane (8 ml),and m-chloroperbenzoic acid (50%, 156 mg, 0.45 mmol) was added thereto,followed by stirring at room temperature for 5 hours. A 10% aqueoussodium hydrogen sulfite solution was added to the reaction mixture, andthe mixture was extracted with chloroform. The organic layer was washedwith an aqueous sodium bicarbonate solution, water and saturated brineand then dried over anhydrous sodium sulfate. The solvent was evaporatedunder a reduced pressure, and the resulting residue was purified bypreparative thin layer chromatography (9:1=chloroform:methanol) toobtain Compound 28 (22 mg, 38%) and Compound 29 (14 mg, 24%).

Compound 28:

¹H NMR (500 MHz, CDCl₃) δ 0.88 (d, J=7.1 Hz, 3H), 1.0-1.9 (m, 10H), 2.64(m, 1H), 2.78 (m, 1H), 2.86 (m, 1H), 2.95 (dd, J=10.9, 6.5 Hz, 1H), 3.02(d, J=4.1 Hz, 1H), 3.18 (dd, J=5.2, 4.0 Hz, 1H), 3.21 (dd, J=8.9, 1.4Hz, 1H), 3.45 (ddd, J=12.0, 10.0, 4.4 Hz, 1H), 3.72 (br s, 1H), 3.82(ddd, J=12.0, 9.1, 6.6 Hz, 1H), 4.34 (s, 1H), 5.13 (br s, 1H).

FABMS m/z 392 (M+H)⁺ C₂₀H₂₅NO₇=391.

Compound 29:

¹H NMR (500 MHz, CDCl₃) δ 0.98 (d, J=7.2 Hz, 3H), 1.0-1.9 (m, 10H), 2.63(m, 1H), 2.75 (m, 1H), 2.78 (m, 1H), 3.01 (dd, J=3.7, 1.4 Hz, 1H), 3.05(m, 1H), 3.11 (dd, J=10.9, 4.4 Hz, 1H), 3.19 (dd, J=9.0, 1.8 Hz, 1H),3.44 (ddd, J=11.9, 9.8, 4.9 Hz, 1H), 3.74 (br s, 1H), 3.89 (m, 1H), 4.36(s, 1H), 5.11 (br s, 1H).

FABMS m/z 392 (M+H)⁺ C₂₀H₂₅NO₇=391.

EXAMPLE 28 Compound 30

In an argon atmosphere, UCS 1025B (15 mg, 0.040 mmol) was dissolved indimethylformamide (2 ml), followed by ice-cooling. Iodomethane (0.025ml, 0.40 mmol) and sodium hydride (4.0 mg, 0.10 mmol) were addedthereto, followed by stirring for 1 hour. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (2:1=hexane:ethyl acetate) to obtain Compound 30(9.4 mg, 58%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (d, J=7.0 Hz, 3H), 1.1-1.9 (m, 10H),2.3-2.7 (m, 3H), 3.2-3.4 (m, 3H), 3.39 (5, 3H), 3.52 (s, 3H), 4.16 (ddd,J=12.1, 9.2, 3.5 Hz, 1H), 4.71 (S, 1H), 5.37 (d, J=9.7 Hz, 1H), 5.60(ddd, J=9.7, 5.0, 2.4 Hz, 1H).

FABMS m/z 404 (M+H)⁺ C₂₂H₂₉NO₆=403.

EXAMPLE 29 Compound 31

UCS 1025A (20 mg, 0.056 mmol) was dissolved in dichloromethane (5 ml),and acetic anhydride (0.026 ml, 0.28 mmol) and 4-dimethylaminopyridine(2.0 mg, 0.017 mmol) were added thereto, followed by stirring at roomtemperature for 20 minutes. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by silica gel column chromatography(3:1=hexane:ethyl acetate) to obtain Compound 31 (15 mg, 67%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (d, J=6.8 Hz, 3H), 1.0-2.0 (m, 10H), 2.14(s, 3H), 2.3-2.8 (m, 3H), 3.2-3.7 (m, 3H), 3.97 (m, 1H), 5.39 (d, J=9.9Hz, 1H), 5.50 (s, 1H), 5.5-5.6 (m, 1H), 11.8 (br s, 1H).

FABMS m/z 402 (M+H)⁺ C₂₂H₂₇NO₆=401.

EXAMPLE 30 Compound 32

UCS 1025A (200 mg, 0.557 mmol) was dissolved in tetrahydrofuran (10 ml),and N-bromosuccinimide (100 mg, 0.562 mmol) was added thereto, followedby stirring at room temperature for 15 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was recrystallized fromethyl acetate to obtain Compound 32 (155 mg, 64%).

¹H NMR (400 MHz, CDCl₃) δ 0.8-1.1 (m, 2H), 0.95 (d, J=7.1 Hz, 3H),1.2-1.3 (m, 2H), 1.5-1.9 (m, 6H), 2.54 (m, 1H), 2.68 (m, 1H), 2.88 (m,1H), 3.20 (dd, J=9.0, 1.7 Hz, 1H), 3.44 (ddd, J=12.0, 9.8, 4.9 Hz, 1H),3.70 (dd, J=11.2, 5.4 Hz, 1H), 3.87 (ddd, J=12.2, 9.5, 6.1 Hz, 1H), 5.21(s, 1H), 5.39 (d, J=10.0 Hz, 1H), 5.57 (ddd, J=9.8, 4.9, 2.7 Hz, 1H).

FABMS m/z 440, 438 (M+H)⁺ C₂₀H₂₄ ⁷⁹BrNO₅=437.

EXAMPLE 31 Compound 33

Compound 32 (33 mg, 0.075 mmol) was dissolved in toluene (10 ml), anddiethylamine (0.078 ml, 0.75 mmol) was added thereto, followed byheating under reflux for 80 minutes. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure, and the resulting residue was purified by preparative thinlayer chromatography (9:1=chloroform:methanol) to obtain Compound 33 (25mg, 76%).

¹H NMR (400 MHz, CDCl₃) δ 0.76 (d, J=7.1 Hz, 3H), 1.0-1.9 (m, 10H),2.4-2.6 (m, 2H), 2.69 (m, 1H), 3.36 (dd, J=9.3, 2.2 Hz, 1H), 3.40 (m,1H), 3.95 (m, 1H), 4.05 (dd, J=11.2, 5.5 Hz, 1H), 4.48 (br s, 1H), 5.06(s, 1H), 5.39 (d, J=9.8 Hz, 1H), 5.50 (ddd, J=9.8, 4.6, 2.6 Hz, 1H).

FABMS m/z 440, 438 (M+H)⁺ C₂₀H₂₄ ⁷⁹BrNO₅=437.

EXAMPLE 32 Compound 34

Compound 32 (10 mg, 0.023 mmol) was suspended in methanol (2 ml), andpotassium carbonate (6.3 mg, 0.046 mmol) was added thereto, followed bystirring at room temperature for 20 minutes. A 0.1 mol/L aqueous citricacid solution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure to obtain Compound 34(9.0 mg, quantitative).

¹H NMR (400 MHz, CDCl₃) δ 0.67 (m, 1H), 0.91 (d, J=7.2 Hz, 3H), 1.0-1.9(m, 9H), 2.3-2.5 (m, 2H), 2.68 (m, 1H), 2.81 (dd, J=11.2, 5.7 Hz, 1H),3.19 (dd, J=7.2, 4.6 Hz, 1H), 3.31 (m, 1H), 3.64 (m, 1H), 3.79 (s, 3H),4.11 (s, 1H), 5.37 (d, J=9.7 Hz, 1H), 5.53 (ddd, J=9.7, 4.4, 2.4 Hz,1H).

FABMS m/z 390 (M+H)⁺ C₂₁H₂₇NO₆=389.

EXAMPLE 33 Compound 35

Compound 33 (20 mg, 0.046 mmol) was suspended in methanol (4 ml), andpotassium carbonate (13 mg, 0.094 mmol) was added thereto, followed bystirring at room temperature for 30 minutes. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure to obtain Compound 35 (11 mg, 61%).

¹H NMR (400 MHz, CDCl₃) δ 0.85 (d, J=7.3 Hz, 3H), 0.9-1.8 (m, 10H), 2.38(m, 1H), 2.64 (m, 1H), 2.88 (m, 1H), 3.16 (dd, J=7.6, 0.9 Hz, 1H), 3.23(m, 1H), 3.42 (dd, J=11.3, 5.5 Hz, 1H), 3.71 (s, 3H), 3.74 (m, 1H), 4.17(s, 1H), 5.39 (d, J=10.0 Hz, 1H), 5.57 (ddd, J=9.8, 4.6, 2.4 Hz, 1H).

FABMS m/z 390 (M+H)⁺ C₂₁H₂₇NO₆=389.

EXAMPLE 34 Compound 36

Compound 32 (438 mg, 1.00 mmol) was suspended in allyl alcohol (15 ml),and potassium carbonate (276 mg, 2.00 mmol) was added thereto, followedby stirring at room temperature for 80 minutes. An aqueous ammoniumchloride solution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure, and the resultingresidue was purified by silica gel column chromatography(2:1=hexane:ethyl acetate) to obtain Compound 36 (188 mg, 45%).

¹H NMR (400 MHz, CDCl₃) δ 0.86 (m, 1H), 0.92 (d, J=7.2 Hz, 3H), 1.0-1.9(m, 9H), 2.3-2.5 (m, 2H), 2.68 (m, 1H), 2.81 (dd, J=11.2, 5.8 Hz, 1H),3.2-3.4 (m, 2H), 3.67 (m, 1H), 3.82 (m, 1H), 4.09 (s, 1H), 4.68 (m, 2H),5.2-5.4 (m, 3H), 5.53 (ddd, J=9.7, 4.4, 2.6 Hz, 1H).

FABMS m/z 416 (M+H)⁺ C₂₃H₂₁NO₆=415.

EXAMPLE 35 Compound 37

In an argon atmosphere, Compound 36 (176 mg, 0.424 mmol) was dissolvedin tetrahydrofuran (10 ml), followed by ice-cooling. Pyrrolidine (0.106ml, 1.3 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.021mmol) were added thereto, followed by stirring at 0° C. for 4 hours. Anaqueous ammonium chloride solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine and then dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure, andthe resulting residue was purified by silica gel column chromatography(9:1=chloroform:methanol) to obtain Compound 37 (48 mg, 30%).

¹H NMR (400 MHz, CDCl₃) δ 0.7-3.8 (m, 20H), 4.21 (br s, 1H), 5.37 (d,J=9.9 Hz, 1H), 5.50 (s, 1H), 5.52 (m, 1H).

FABMS m/z 376 (M+H)⁺ C₂₀H₂₅NO₆=375.

EXAMPLE 36 Compound 38

Compound 37 (20 mg, 0.053 mmol) was dissolved in dichloromethane (4 ml),and 2-chloro-1-methylpyridinium iodide (68 mg, 0.27 mmol) anddiethylamine (0.028 ml, 0.27 mmol) were added thereto, followed bystirring at room temperature for 12 hours. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (19:1=chloroform:methanol) to obtain Compound 38(19 mg, 83%).

¹H NMR (400 MHz, CDCl₃) δ 0.66 (m, 1H), 0.91 (d, J=7.2 Hz, 3H), 1.0-1.9(m, 9H), 1.18 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 2.31 (m, 1H),2.47 (m, 1H), 2.72 (m, 1H), 2.81 (dd, J=11.2, 5.7 Hz, 1H), 3.2-3.4 (m,5H), 3.65 (m, 1H), 3.78 (m, 1H), 3.89 (s, 1H), 5.35 (d, J=9.7 Hz, 1H),5.52 (ddd, J=9.7, 4.4, 2.6 Hz, 1H).

FABMS m/z 431 (M+H)⁺ C₂₄H₃₄N₂O₅=430.

EXAMPLE 37 Compounds 39 and 40

UCS 1025A (4.8 mg, 0.013 mmol) was dissolved in methanol (1 ml) andthen, under ice-cooling, excess diazomethane (an ether solution, 1 ml)was added thereto, and the mixture was allowed to stand for 30 minutes.The reaction mixture was concentrated and then the residue was purifiedby preparative thin layer chromatography (1:1=hexane:ethyl acetate) toobtain Compound 39 (1.3 mg, 24%) and Compound 40 (2.3 mg, 45%).

Compound 39:

¹H NMR (500 MHz, CDCl₃) δ 0.73 (td, J=12.0, 3.7 Hz, 1H), 0.86 (d, J=7.1Hz, 3H), 1.0-1.9 (m, 9H), 2.42 (m, 1H), 2.64 (m, 1H), 2.68 (m, 1H), 3.13(dd, J=11.2, 5.6 Hz, 1H), 3.18 (dd, J=7.6, 1.5 Hz, 1H), 3.33 (ddd,J=12.2, 9.5, 2.7 Hz, 1H), 3.77 (dd, J=8.3, 5.9 Hz, 1H), 3.81 (s, 3H),4.21 (d, J=2.0 Hz, 1H), 5.37 (d, J=9.8 Hz, 1H), 5.55 (ddd, J=9.8, 4.6,2.7 Hz, 1H), 6.70 (br s, 1H).

FABMS m/z 416 (M+H)⁺ C₂₂H₂₉N₃O₅=415.

Compound 40:

¹H NMR (500 MHz, CDCl₃) δ 0.78 (d, J=7.1 Hz, 3H), 0.85. (m, 1H), 1.08(m, 1H), 1.2-1.4 (m, 2H), 1.54 (m, 1H), 1.7-1.8 (m, 4H), 1.86 (m, 1H),2.31 (s, 3H), 2.39 (s, 1H), 2.51 (ddd, J=13.2, 10.8, 2.1 Hz, 1H), 2.60(m, 1H), 2.72 (ddt, J=13.2, 6.8, 9.3 Hz, 1H), 3.18 (d, J=6.8 Hz, 1H),3.36 (ddd, J=10.8, 9.2, 2.1 Hz, 1H), 3.57 (s, 3H), 3.71 (dd, J=11.3, 5.7Hz, 1H), 3.82 (td, J=10.8, 9.3 Hz, 1H), 5.37 (br d, J=9.8 Hz, 1H), 5.52(ddd, J=9.8, 5.1, 2.6 Hz, 1H).

FABMS m/z 388 (M+H)⁺ C₂₂H₂₉NO₅=387.

EXAMPLE 38 Compound 41

UCS 1025A (2.0 mg, 0.0056 mmol) was dissolved in a mixed solvent of Trisbuffer (50 mmol/L, pH 8.0, 2.0 ml) and methanol (0.2 ml), followed byice-cooling. An aqueous 2-mercaptoethanol solution (500 mmol/L, 0.020ml) was added thereto, followed by stirring for 30 minutes. The mixturewas acidified by adding a phosphate buffer (1.0 mol/L, pH 5.9, 0.2 ml)and then extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and concentrated under a reduced pressure, andthe resulting residue was purified by silica gel column chromatography(100:1=ethyl acetate:acetic acid) to obtain Compound 41 (2.0 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ 0.81 (d, J=7.1 Hz, 3H), 0.9-1.9 (m, 10H), 2.42(dd, J=13.3, 8.0 Hz, 1H), 2.56 (m, 1H), 2.6-2.8 (m, 2H), 2.97 (dt,J=14.5, 5.9 Hz, 1H), 3.04 (d, J=6.5 Hz, 1H), 3.34 (t, J=10.5 Hz, 1H),3.47 (dd, J=11.3, 5.8 Hz, 1H), 3.68 (dt, J=10.5, 8.0 Hz, 1H), 3.89 (t,J=5.9 Hz, 2H), 3.92 (d, J=10.5 Hz, 1H), 4.43 (d, J=10.5 Hz, 1H), 5.40(d, J=9.8 Hz, 1H), 5.54 (ddd, J=9.8, 4.5, 2.6 Hz, 1H).

FABMS m/z 436 (M−H)⁻ C₂₂H₃₁NO₆S=437.

EXAMPLE 39 Compound 42

Compound 42 (2.0 mg, 79%) was obtained in a manner similar to that inExample 38 using 3-mercaptopropanol instead of 2-mercaptoethanol.

¹H NMR (400 MHz, CDCl₃) δ 0.82 (d, J=7.1 Hz, 3H), 0.95 (m, 1H), 1.0-2.0(m, 11H), 2.42 (dd, J=12.0, 7.8 Hz, 1H), 2.5-2.9 (m, 4H), 3.01 (d, J=6.4Hz, 1H), 3.32 (t, J=10.8 Hz, 1H), 3.43 (dd, J=11.2, 5.9 Hz, 1H), 3.73(dt, J=10.8, 8.3 Hz, 1H), 3.75 (m, 1H), 3.80 (m, 1H), 3.84 (d, J=10.3Hz, 1H), 4.35 (d, J=10.3 Hz, 1H), 5.41 (d, J=10.0 Hz, 1H), 5.55 (ddd,J=10.0, 4.6, 2.7 Hz, 1H).

EXAMPLE 40 Compound 43

Compound 43 (2.0 mg, 0.80%) was obtained in a manner similar to that inExample 38 using 1-propanethiol instead of 2-mercaptoethanol.

¹H NMR (500 MHz, CDCl₃) δ 0.81 (d, J=7.1 Hz, 3H), 0.93 (m, 1H), 0.99 (t,J=7.3H, 3H), 1.0-1.9 (m, 1H), 2.46 (dd, J=12.8, 7.8 Hz, 1H), 2.5-2.8 (m,4H), 2.99 (d, J=6.9 Hz, 1H), 3.31 (t, J=11.0 Hz, 1H), 3.43 (dd, J=11.2,5.8 Hz, 1H), 3.70 (dt, J=11.0, 8.6 Hz, 1H), 3.77 (d, J=9.7 Hz, 1H), 4.35(d, J=9.7 Hz, 1H), 5.41 (d, J=9.8 Hz, 1H), 5.55 (ddd, J=9.8, 4.6, 2.7Hz, 1H).

FABMS m/z 436 (M+H)⁺ C₂₃H₃₃NO₅S=435.

EXAMPLE 41 Compound 44

UCS 1025B (38 mg, 0.10 mmol) was dissolved in methanol (3 ml), followedby ice-cooling. Sodium borohydride (9.0 mg, 0.22 mmol) was addedthereto, followed by stirring at room temperature for 1 hour. Water wasadded to the reaction mixture, and the mixture was extracted twice withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the resulting residue was purified by silica gelcolumn chromatography (19:1=chloroform:methanol) to obtain Compound 44(25 mg, 66%).

FABMS m/z 378 (M+H)⁺ C₂₀H₂₇NO₆=377.

INDUSTRIAL APPLICABILITY

According to the present invention, novel UCS 1025 derivatives havingantitumor activity or antibacterial activity can be provided.

1. A compound represented by formula (I):

wherein R¹ represents hydrogen, or lower alkyl, NR⁹R¹⁰, SR¹² or OR¹³; R²is hydrogen or is combined with R³ to represent a bond; R³ representshydrogen, OR¹⁵ or halogen, or is combined with R² to represent a bond;R⁴ represents hydrogen, CO₂R¹⁶ or CONR¹⁷R¹⁸; R⁵ represents hydrogen oris combined with R⁶ to represent a bond; R⁶ represents hydrogen or OR¹⁹,or is combined with R⁵ to represent a bond; R⁷ represents hydrogen or iscombined with R⁸ to represent ═O; R⁸ represents hydroxy or is combinedwith R⁷ to represent ═O; R⁹ and R¹⁰ independently represent hydrogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkenyl, substituted or unsubstituted lower alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aralkyl or OR¹¹, orR⁹ and R¹⁰ are combined together with the adjacent N to form asubstituted or unsubstituted heterocyclic ring; R¹¹ represents hydrogenor lower alkyl; R¹² represents hydrogen, substituted or unsubstitutedlower alkyl, substituted or unsubstituted lower alkenyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted aralkyl; R¹³ represents hydrogen,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkenyl, or substituted or unsubstituted lower alkynyl; R¹⁵represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aralkyl, or substituted orunsubstituted lower alkanoyl; R¹⁶ represents hydrogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted lower alkynyl, substituted or unsubstitutedaryl, or substituted or unsubstituted aralkyl; R¹⁷ and R¹⁸ independentlyrepresent hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aryl, or substituted orunsubstituted aralkyl, or R¹⁷ and R¹⁸ are combined together with theadjacent N to form a substituted or unsubstituted heterocyclic ring; R¹⁹represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted lower alkenyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted aralkyl, or substituted orunsubstituted lower alkanoyl; ---- represents a single bond or a doublebond; and a represents an oxygen atom or both carbon atoms to which a isbound are joined by a double bond, or a pharmaceutically acceptable saltthereof with the proviso that R¹ does not represent hydrogen when R² andR³ are combined to represent a bond, R⁴ represents carboxy, R⁵represents hydrogen, R⁶ represents hydroxy, R⁷ and R⁸ are combined torepresent ═O, and ---- and a both represent a single bond.
 2. Thecompound according to claim 1, wherein R¹ is hydrogen, NR⁹R¹⁰, SR¹² orOR¹³, or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1 or 2, wherein R⁷ and R⁸ are combined to represent═O, or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 3, wherein R⁴ is hydrogen, or a pharmaceuticallyacceptable salt thereof.
 5. A method for treating bacterial infection,comprising administrating the compound or the pharmaceuticallyacceptable salt thereof according to claim 1 or 2 to a patient in needthereof.
 6. A method for treating a renal carcinoma, comprisingadministrating the compound or the pharmaceutically acceptable saltthereof according to claim 1 or 2 to a patient in need thereof.
 7. Amedicament comprising, as an active ingredient, the compound or thepharmaceutically acceptable salt thereof according to claim 1 or 2 and apharmaceutically acceptable excipient.
 8. The method according to claim6, wherein the renal carcinoma is malignant.
 9. A method ofmanufacturing an agent for treating renal carcinomas, comprisingselecting the compound or the pharmaceutically acceptable salt thereofaccording to claim 1 or 2 and admixing said compound or salt with apharmaceutically acceptable excipient.
 10. The compound according toclaim 1 or 2, wherein R² and R³ are combined to represent a bond, or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 10, wherein R⁷ and R⁸ are combined to represent ═O, or apharmaceutically acceptable salt thereof.
 12. The compound according toclaim 3, wherein R⁴ is CO₂R¹⁶, or a pharmaceutically acceptable saltthereof.
 13. The compound according to claim 3, wherein R⁴ is CONR¹⁷R¹⁸,or a pharmaceutically acceptable salt thereof.